Androgen deprivation therapy
(ADT) with a gonadotropinreleasing
hormone agonist is
the cornerstone of treatment for metastatic
prostate cancer. Patterns of care
have changed dramatically over the
past decade, and gonadotropin-releasing
hormone agonists are now routinely
administered to men without
radiographic evidence of metastases.
These agents account for about onethird
of Medicare expenditures for the
treatment of prostate cancer[1]; in
1999, that portion exceeded $800 million.
The routine use of gonadotropin-
releasing hormone agonists in men
with nonmetastatic prostate cancer increases
the importance of understanding
and preventing treatment-related
adverse effects. In this issue of
ONCOLOGY, Dr. Holzbeierlein and
colleagues provide a timely summary
of the adverse effects of ADT.
Osteoporosis
Androgen deprivation therapy decreases
bone mineral density and increases
risk of fracture in men with
prostate cancer. Although commonly
compared to menopausal bone loss,
treatment-related bone loss in prostate
cancer patients is distinct from
postmenopausal bone loss in two important
ways. First, the rate of bone
loss during initial ADT for prostate
cancer is substantially higher than the
rate of bone loss during early menopause.
Second, high rates of bone loss
appear to persist indefinitely during
ADT, whereas bone loss slows in late
menopausal women.
Despite these important clinical
distinctions, the mechanisms of bone
loss are similar in men receiving ADT
and postmenopausal women. Available
evidence indicates that estrogen
is more important than testosterone
for maintaining bone mass in both
men and women. In addition, bone
loss in hypogonadal men and postmenopausal
women is characterized
by osteoclast activation and increased
bone turnover.
Screening for osteoporosis by measurement
of bone mineral density is
necessary in this setting, because prostate
cancer patients on ADT are at
high risk for osteoporosis and will
remain asymptomatic until they experience
a fracture. Given interpatient
differences in peak bone mass and
rates of bone loss during ADT, some
but not all men will develop osteoporosis
during treatment. Vitamin D deficiency
and inadequate dietary calcium
intake are common, and I recommend
calcium (500-1,000 mg/d) and vitamin
D (400 IU/d) supplementation
for all men receiving ADT.
I also recommend bisphosphonates
for men with either a clinical fracture,
osteopenia prior to ADT (bone mineral
density T score between -1.0 and
-2.5), or osteoporosis (T score less
than -2.5). Bisphosphonates may also
be appropriate for men who have normal
bone mineral density but are at
high risk for falls.
Body Composition
Prospective studies have shown
that gonadotropin-releasing hormone
agonists increase fat mass and decrease
lean body mass. The magnitude
of the changes is remarkable,
with most studies reporting approximately
a 10% increase in fat mass.
Treatment-related changes in body
composition appear within the first
few months, but in contrast to the
ongoing high rates of bone loss,
changes in body composition appear to slow during long-term treatment.
These changes may lead to frailty and
a risk of falls in older men, as well as
fatigue, insulin resistance, and increased
cardiovascular disease risk.
Exercise is a reasonable but unproven
strategy to mitigate the adverse
body composition effects of
ADT. Resistance exercise training increases
muscle size and strength in
men with other chronic diseases and
normal or moderately low serum testosterone
concentrations. It also reduces
fatigue in men receiving ADT for
prostate cancer,[2] but its effects on
body composition have not been adequately
evaluated in this setting.
Insulin Resistance and
Cardiovascular Disease Risk
Insulin resistance is a common
metabolic abnormality that characterizes
individuals with type 2 diabetes
and is prevalent in about 20% to 25%
of nondiabetic individuals. The condition
is an independent risk factor
for cardiovascular disease and is associated
with a variety of abnormalities
related to increased cardiovascular
disease risk, including central obesity,
hypertension, elevated triglyceride
levels, decreased high-density-lipoprotein
cholesterol levels, and elevated
markers of fibrinolysis. This
constellation of abnormalities is collectively
known as the insulin resistance
syndrome or the metabolic
syndrome.[3,4]
The phenotype of men receiving
ADT shares many but not all of the
features associated with the insulin
resistance syndrome. Androgen deprivation
therapy increases weight and
fat mass as well as fasting plasma
insulin levels,[5] a marker of insulin
resistance. No other study has evaluated
treatment-related changes in fasting
plasma insulin levels or more
reliable measures of insulin sensitivity.
Additional research is needed to better characterize this metabolic syndrome
and the potential impact of
ADT on cardiovascular disease risk.

Disclosures

The author has no
significant financial interest or other relationship
with the manufacturers of any products
or providers of any service mentioned in this
article